title: Small molecule recognition of c-Src via the Imatinib-binding conformation.
abstract: The cancer drug, Imatinib, is a selective Abl kinase inhibitor that does not inhibit the closely related kinase c-Src. This one drug and its ability to selectively inhibit Abl over c-Src has been a guiding principle in virtually all kinase drug discovery efforts in the last 15 years. A prominent hypothesis explaining the selectivity of Imatinib is that Abl has an intrinsic ability to adopt an inactive conformation (termed DFG-out), whereas c-Src appears to pay a high intrinsic energetic penalty for adopting this conformation, effectively excluding Imatinib from its ATP pocket. This explanation of the difference in binding affinity of Imatinib for Abl versus c-Src makes the striking prediction that it would not be possible to design an inhibitor that binds to the DFG-out conformation of c-Src with high affinity. We report the discovery of a series of such inhibitors. We use structure-activity relationships and X-ray crystallography to confirm our findings. These studies suggest that small molecules are capable of inducing the generally unfavorable DFG-out conformation in c-Src. Structural comparison between c-Src in complex with these inhibitors allows us to speculate on the differential selectivity of Imatinib for c-Src and Abl.
authors.affiliation: Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, Genentech Hall, 600 16(th) Street, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Arvin C
authors.initials: AC
authors.lastname: Dar
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lopez
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
mesh_terms: D001549:Benzamides; D018360:Crystallography, X-Ray; D000068877:Imatinib Mesylate; D008958:Models, Molecular; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry*; D011485:Protein Binding; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry*
chemical_list: D001549:Benzamides; D004364:Pharmaceutical Preparations; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016392:Proto-Oncogene Proteins pp60(c-src)